Chemotherapy and radiotherapy are the primary treatment means for cancers. However, the two treatment means face a common challenge in clinical practice, i.e. treatment-induced side effects and insensitivity of tumor to treatment. Since the two treatment methods lack selectivity among normal cells and cancer cells and result in damage of normal cells and produce side effects, patients often die of complications induced by radiotherapy and chemotherapy, and the survivors' life quality is also very poor. In addition, the adverse effects always limit the therapeutic dose, and greatly affect the therapeutic effect.
Based on the current status and the present bottleneck of the field of therapy against tumor, the clinical use of cytoprotective agents and the development of targeted anti-cancer drugs seem to partially alleviate the side effects of treatment to a certain extent in recent years. However, clinical data confirmed that the new generations of targeted anti-cancer drugs still have two major drawbacks: 1. patients are prone to tolerance to the treatment; 2. targeted anti-cancer drugs are expensive and narrow in indications. Therefore, traditional treatment means still dominate for about 95% of patients with tumor. The commercially-available cytoprotective agents such as amifostine are very narrow in indications, and they have significant interference with therapeutic effects. Traditional antioxidants such as glutathione and Vit-E have been proven to be ineffective clinically.
Another difficult problem is that the tumor cells will produce tolerance in the process of treatment. The existing radiotherapy sensitizers, such as sodium glycididazole, are only suitable for radiation-sensitized therapy of a part of tumors, and they have a narrow range of indications and multiple contraindications. Moreover, they have evident cardiac toxicity as well as the drawback of promoting oxidative damage of normal tissues.
Existing products either only have a sensitizing effect or only have the function of reducing side effects, so there is a clinical need to develop a new drug that can alleviate side effects while enhance the sensitivity of tumors to treatment. The source of resistance of tumors to treatment lies in the overactivity of enzymes associated with proliferation. It has been found in studies that overexpression of COX2 by tumor cells is one of the causes for the resistance of tumors to treatment, and inhibition of COX2 expression can restore the sensitivity of the tumors to the treatment to a certain extent. However, clinical experimental results have shown that the side effects on cardiovascular system induced by COX2 inhibitors limit the use thereof although selective COX2 inhibitors have certain sensitizing effect. The inventor has found in the latest study that COX1 activity is actually the key factor that determines whether the tumor cells are sensitive to treatment. That is to say, the purpose of enhancing the sensitivity of tumors to treatment at the greatest extent can only be achieved truly by inhibiting COX1 and COX2 at the same time. However, the existing drugs that can inhibit both COX1 and COX2 at the same time will lead to a strong side effect of gastrointestinal bleeding and a certain degree of hepatotoxicity, greatly restricting its practical application. Accordingly, there is an urgent need in the art for the development of a novel drug capable of simultaneously inhibiting COX1 and COX2 and overcoming the above-mentioned gastrointestinal irritation and hepatotoxicity.
In addition, drugs against oxidative injury are often used in the meantime during the process of cancer treatment to relieve the treatment-induced side effects. However, due to the first pass effect of liver, the bioavailability for oral administration of some conventional drugs against oxidative injury is poor, and thus the in vivo anti-oxidant effect thereof is unsatisfactory. It is also highly desirable to develop drugs which have a high bioavailability and can maintain their effect of alleviating side effects.
A novel compound is developed in the present invention, and it effectively solves the two bottlenecks that the treatment of tumors faces, i.e. treatment resistance (tolerance) and side effect. Specifically, the compound developed by the present invention does not induce significant gastrointestinal irritation, it can avoid hepatotoxicity, and at the same time have excellent tumor-sensitizing effect and the effect of protecting normal cells from side effects of cancer treatment. The inventors performed experimental treatments on mice with colon cancer using the compound. The results show that the volume of tumor in the mice administrated with the compound is significantly decreased and that the damage of normal tissues is greatly reduced.
In addition, the applicant has also found that the compound of the present invention can be used as a medicament for treating a tumor, and used alone or in combination with other drugs for treatment of tumors and can achieve the effect of inhibiting tumor cell proliferation or killing tumor cells.